The goal of this project is to develop a small molecule drug that modulates the proliferation of proinflammatory bacteria in the gut as a novel therapeutic for the treatment of inflammatory bowel disease (IBD). Over 1.6 million Americans suffer from IBD, an umbrella term to describe chronic inflammation of all or part of the digestive tract, including Crohn?s disease and ulcerative colitis. IBD is a complex immune disorder that can be caused by genetics, environment, aberrant immune response and disruption of the digestive tract microbiota. IBD ranks as one of the five most expensive GI disorders, with an annual direct medical cost burden between $11-28 billion, approximately half of which are for prescription drugs. Most current strategies to manage or treat IBD involve suppressing the immune system, however many of these drugs are not intended for long term use, and others have no effect in up to half of patients treated. Thus, currently available therapies do not meet the needs of all patients, and new treatment approaches are needed. We are developing novel ?symbiotic drugs? that target one of the known causes of digestive tract inflammation: the microbiome. Our pilot studies demonstrate the feasibility of our microbiome-targeting approach in slowing the growth and proliferation of proinflammatory Enterobacteriaceae bacteria without compromising the growth of protective bacteria. In this proposal we will confirm and extend our pilot studies with the development of cell based assays to screen our library of microbiome-targeting small molecule drugs (Aims 1 and 2). We will select the most potent inhibitors of Enterobacteriaceae proliferation and evaluate their in vivo effects including the modulation of (1) clinical and (2) molecular markers of IBD, as well as their (3) antiproliferative efficacy in a rat experimental m odel of intestinal colitis (Aim 3). Because Enterobacteriaceae expansion is a conserved feature of IBD, independent of genetic variants or environmental triggers, our therapeutic approach is expected to have broad utility in IBD treatment. Our approach uniquely recognizes the multifactorial nature of IBD pathogenesis with the development of microbiota-specific, rather than host-specific, therapeutics.